Title

Author

Defense Date

1966

Document Type

Thesis

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

John Andrako

Abstract

Numerous and diverse physiological actions are found among 2-oxazoline compounds. No reports of the synthesis or biological testing of 4-spiro-2-aryl-2-oxazolines were found in the literature. On the basis of the known pharmacological activities of certain aza- and diazaspirans, it was felt that 4-spiro-2-aryl-2-oxazolines should possess medicinal activity. In particular, it was reasoned that the combination in a bicyclic spiro structure of the 2-oxazoline ring with rings systems commonly found in synthetic antitussive compounds might result in active antitussive agents.

The aim of this research was the synthesis of a series· of 2-aryl-2-oxazoline-4-spirocyclopentanes and a series of 1'-methyl-2-aryl-2-oxazoline-4-spiro-4’-piperidines. Six members were to be prepared in each series in which the aryl group represents respectively, a phenyl, a p-chloro, p-methyl, p-nitro, p-ethoxy, and p-dimethylaminophenyl radical.

With the exception of the p-dimethylamino derivative, acylation of 1-aminocyclopentane-1-carboxylic acid gave the corresponding amido acids, the methyl esters of which were reduced with lithium borohydride to the corresponding amide-alcohols. Dicyclohexylcarbodiimide was employed to produce 1-(p-dimethylaminohenzamido)-1-carbomethoxycyclopentane from p-dimethylaminobenzoic acid and 1-amino-1-carbomethoxycyclopentane after unsuccessful attempts to prepare it by the mixed carbonic anhydride method. Each amide-alcohol, on treatment with hydrogen chloride in chloroform, rearranged by N to 0 acyl migratilon to the corresponding 1-amino-1-cyclopentylmethyl p-substituted benzoate hydrochloride. On treatment with base these compounds rearranged to the original amide-alcohols by 0 to N acyl migration. This sequence of reactions confirmed the structure of the amide-alcohols.

Treatment of each amide-alcohol with thionyl chloride afforded the corresponding, 2-aryl-2-oxazoline-4-spirocyclopentanes in good yields. The structure of these compounds was confirmed in each case by the infrared spectra and elemental analyses of the oxazoline and/or its hydrochloride. Futhermore, the structure of 2-(p-ethoxyphenyl) -2-oxazoline-4-spirocyclopentane was confirmed by a proton magnetic resonance spectrum.

Each oxazoline compound ( except the p-dimethylamlnoderivative) was converted to the corresponding 1-(p-substitutedbenzamido)-1-chloromethylcyclopentane by treatment with a saturated solution of hydrogen chloride in dioxane. Each chloroamide compound ( except the p-nitro derivative) was converted to the corresponding oxazoline by treatment with alkali in order to provide further evidence for the oxazoline structure of the products isolated from the thionyl chloride reactions.

4-Amino-l-mothylpiporidine-4-carboxylic acid was obtained by both acid and alkaline hydrolysis of the corresponding hydantoin. 4-Amino-4-hydroxymethyl-l-methylpiperidine, which was obtained by the reduction of 4-amino-4-carbomethoxy-l-methylpiperidine with lithium borohydride, was treated with benzoyl chloride and p-methylbenzoyl chloride to give respectively, 4-benzamido- 4-hydroxymethyl-l-methylpiperidine and 4-(p-methylbenzamido)- 4-hydroxymethyl-l-methylpiperidine. 4-Benzamido- 4-hydroxymethyl-l-methylpiperidine was also obtained by the reduction with lithium borohydride of 4-benzamido- 4-carbomethoxy-1-methylpiperidine which was prepared by benzoylation of 4-amino-4-carbomethoxy-l-methylpiperidine. 1'-Methyl-2-phenyl- and 1’-methyl-2-(p-methylphenyl)-2-oxazoline-4-spiro-4'-piperidine were prepared by treatment of the corresponding amido-alcohols with thionyl chloride.